Necrotic cell death is a common response of the liver to hepatotoxic agents and represents an irreversible form of damage to individual liver cells. While the mechanisms by which hepatotoxic agents lead to necrosis remain to be fully understood, progress has been made in understanding the biochemical pathways involved. Necrotic cell death occurs when a chemical or it's metabolite react with critical cellular systems resulting in ion dysregulation, mitochondrial dysfunction and oxidative stress [1–3]. The acute disruption of these normal cellular events in effect leads to ATP depletion. This loss of energy within the cell distinguishes necrosis from the other classification of cell death known as apoptosis. When cells undergo apoptosis or programmed cell death, the cell requires an energy level capable of triggering special metabolic, signal transduction and gene regulation pathways that systematically shut down the cell. Necrosis occurs when the ATP levels falls below the threshold required for these processes and the cell is driven into a passive state of cellular chaos that culminates in cell death [4]. Thus, although these two forms of cell death are distinct, they can share initiating pathways depending on the how sharply the ATP levels decline. Such can be seen with the induction of the mitochondrial permeability transition (MPT), a mechanism that causes mitochondrial failure. The MPT will lead to necrosis if ATP is depleted or apoptosis if there are sufficient amounts available to initiate a caspase cascade [5].
Chemical insult that produces necrosis of the liver can be either nonzonal or zonal. Zonal necrosis is separated into zones 1, 2 and 3 based on the region of the lobule affected. Different hepatotoxic agents preferentially target specific zones [6]. This research project report specifically deals with those agents that produced zone 3 or centrilobular necrosis. This is the most commonly affected area of the liver for hepatotoxic agents producing zonal necrosis. Zones 1–3 are distinguishable in terms of blood flow, oxygen content, bile flow and ratio of intoxication versus detoxification pathways. Factors such as these explain the specificity of hepatotoxic agents for particular zones. Acetaminophen and carbon tetrachloride (CCL4) are examples of agents that produce mainly zone 3 necrosis once they are converted to reactive metabolites. This can be attributed to the high degree of regional organization of agent specific cytochrome P450's within the liver [7]. The supply of oxygen available to the cell has also been shown to be a factor for zone 3 necrosis producing agents. Zone 3 is the region of the liver that is furthest from the arterial blood supply receiving the least supply of oxygen. When CCl4 is metabolized to its reactive metabolite CCl3, the reduction reaction is inhibited by oxygen, favoring a necrotic response in the centrilobular area [7].
Liver cell necrosis can evoke a range of responses within the liver that depend on the severity of insult. These responses range from regeneration of necrotic tissue with restoration of full liver function to concomitant loss of liver function, liver failure and death [8]. In the process, necrosis may trigger the development of other liver diseases. Recurring bouts of necrosis and repair may result in disruption of the structure of the liver and result in subacute hepatitis, chronic hepatitis or even cirrhosis [9]. In this process, inflammatory cells stimulate the deposition of collagen around hepatocytes causing alteration in hepatic function and blood flow [10]. There is also evidence that necrosis may play a role in the induction of early hepatocellular carcinoma through compensatory liver regeneration. Diethylnitrosamine and Fumonisin B(1) are two examples of compounds that show evidence of producing hepatocellular carcinoma in rats through a sequence of events that begin with necrosis [11–13]. Thus the benefit of obtaining marker genes predictive of hepatic zone 3 necrosis stem from its participation in the pathogenesis of other liver diseases as well as it being an early indicator of hepatic toxicity.